It’s not easy to push the explosive terror of norovirus out of the public square. It takes another virus that’s even more worrying and even more adept at spreading suffering around the world.

I speak, of course, of influenza.

This winter’s influenza season came early to the Northern Hemisphere and made a splashy debut. By the end of last week, the Centers for Disease Control reported widespread flu in 47 out of 50 states in the U.S. Some stocks of vaccines were running out. Some parts of the U.S. show signs of having hit their peak, but other places, like California, haven’t yet really experienced the full wallop of flu season. So we could be looking at several more weeks of serious trouble. Europe, meanwhile, is seeing high levels of flu infections, too. (I spoke today about the flu on KPCC–listen here.)

What makes all this all the more nerve-wracking is that influenza isn’t even bringing its A game right now. We’re not dealing with a new, super-virulent strain of influenza akin to the 1918 “Spanish flu,” which killed 50 million people worldwide. This is just regular seasonal flu–a stew of old-timer flu strains that slosh out of the tropics, heading north and south as conditions permit, and killing roughly half a million people every year. The fact that this year’s seasonal flu has overwhelmed us (shutting down some hospitals, in fact) doesn’t bode well for the inevitable moment some time in the future when we do come face to face with a much meaner flu strain.

In the face of all these sobering facts, it’s easy to fall under the virus’s spell and be filled with awe. After all, with a dozen or so genes, it manages to replicate itself by the trillions and circle the globe in weeks.

A team of scientists led by Jonathan Yewdell at the National Institute of Allergic and Infectious Diseases recently asked a simple question: what are the odds that an influenza virus is in good working order?

In order to infect a cell, flu viruses need to produce a protein called hemagglutinin, which forms knobs on the virus’s surface and latches onto host cells. Once the virus gets inside the cell, other proteins shut down the host cell’s natural antiviral defenses, help guide the cell to make new genes, and then help package them up. Another protein on the shell of flu viruses, called neuraminidase, opens up the host cell to allow the viruses to escape.

Yewdell and his colleagues infected cells with flu viruses and then surveyed them for these essential proteins. Time and again, they found viruses that lacked at least one of them. They tested out these defective viruses and found they failed to work as a virus should. As they report in an upcoming paper in the Journal of Virology, almost ninety percent are incapable of replicating because they’re missing at least one essential protein.

This is not some general feature of all viruses. Yewdell and his colleagues ran a similar experiment with another species, called vesicular stomatitis virus. It almost always managed to do the bare minimum and produce new viruses with all its essential proteins. Influenza stands out in its incompetence.

Yewdell and his colleagues offer up a few possible explanations for this incompetence.

–Influenza viruses mutate like mad. Mutations may be so common and so devastating that the vast majority of viruses end up unable to make at least one essential protein.

–It’s also possible that when a virus invades a host cell, it fails to get the cell to make all the essential proteins that new viruses will need. Nobody knows the success rate for this step of influenza infection is.

–Another possible source of failure has to do with the way genes are arranged in the flu virus. Rather than being one continuous string of genetic material, the flu virus genome is broken up into eight segments. A new virus needs to swallow up a copy of all eight segments in order to have the genes for all its essential proteins. Flu viruses may be sloppy in assembling their genes.

It’s possible that all three causes are in play, or that influenza’s incompetence has yet another source. Whatever the reason, the simple fact remains: nine out of ten flu viruses are fundamental failures. Which raises the question of why there’s any flu at all.

Flu still manages to be a major threat to public health because viruses can handle failure very well. If only ten percent of viruses have all their essential proteins, they can carry on the flu virus legacy by replicating exponentially. And it may well be that the incompetent flu viruses can replicate as well. Two or more flu viruses sometimes infect the same cell at once. They may be able to help each other out, making up for the defects in their fellow viruses with their own working proteins. If one virus can’t protect itself against a cell’s defenses, another can. If one virus doesn’t have the proteins it needs to escape the host cell, another virus may open the door.

It’s almost sweet to imagine flu viruses helping each other overcome their collective weaknesses. Until, of course, that spirit of cooperation lands you in bed with a fever and the sort of aches you expect from a boxing match.

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13 thoughts on “Influenza: Our Incompetent Enemy”

Was the virulence of the Spanish flu due to some great adaptation it had? Or was it due to immune system overresponse creating a cytokine storm? I have heard evidence of the latter, particularly to explain why the preponderance of 1918 victims weren’t the very young or very old as would be expected if the flu were actually overrunning their immune systems.

So I can imagine the Spanish Flu didn’t bring its A game either, but somehow triggered the immune system into believing it did.

P.S. One typo I spotted: “barre minimum”

[CZ: First off, thanks for the proofreading. I’ve fixed the typo. Second, I only meant “bringing its A game” to mean how deadly the virus is this year compared to other years, whatever the reason. The role of a “cytokine storm” in 1918 is still under debate, but it’s clearly an important thing to understand better.]

One might see the ridiculous mutagenicity of the flu as it’s mad genius. Other viruses have been “tipped” over into high enough replication that their virulence drops. And arguably, when influenza has carried extreme mortality (as outlined in the early going of The Great Influenza) it’s mutated to less virulence such that it continued to infect. Unlike, for example, Ebola which can be so fatal that it’s unable to cause a pandemic. The flu doesn’t mean to kill you, it’s just a side effect of the drive to infect. And as with any parasite, it doesn’t do to kill off your hosts too often.

High numbers of apparently defective particles are not found in all viruses, but it is a fairly common phenomenon, especially in RNA viruses- mumps, for example, and, IIRC, many retroviruses.

What’s different here, it appears to me, is that they’ve demonstrated that a large percentage of the particles that would be classified as ‘non-infectious’ by a traditional plaque assay are in fact capable of producing proteins and even particles- it’s just that, since they are missing a protein, without the help of other particles that do have that protein, they will be unable to spread beyond that single, initially infected cell, and thus will not produce a visible plaque.

At high multiplicities of infection, when there are tons of other particles around, this could change the dynamics of the infection significantly- the percentage of infectious particles could increase greatly, because all the defective particles are able to help each other out by genetic complementation.

It’s ‘flu alert’ here in the Philippines and airport officials are closely monitoring arriving passengers for flu and flu-like signs and symptoms. Sweeter it is to see people cooperating to overcome their collective weakness against an unseen enemy.

Ooooppss, seems to me there’s some ‘deletion-mutation’ here: Nobody knows the success rate for this step of influenza infection is ?

I remember reading a few years ago that one of the mysteries of the 1918 pandemic was that the new virulent flu appeared almost simultaneously in America, Europe, India and Australia. Travel at that time was by steamship, thus intercontinental spread by infected persons could not explain the near simultaneous appearance of the disease. What are your thoughts on this issue?

It’s the simplicity of lifes Questions that we are not prepared to accept! (John F K) The R Ready”
Life iz but a simple Question you ask & you will an. Knew understanding is the only way to make up times lost. Open Knowledge by way of you

My grandmother was 23 with 3 small children when she died in 1918. The virology is interesting to me as a non-scientist, but ultimately interesting to me as a person who didn’t have a grandma. We need to also consider the human aspect of it. By the way, it was common to take photographs of people in their coffins in those days. Besides my grandmother’s wedding picture, the only other one I have is her in the coffin with her three small children standing beside it, looking bewildered.

The tenfold variation in the percentage of non-propagating infections in the paper does rather suggest this might be a lab strain artefact. I am dubious about counting foci and surrounding cells by eye and declaring two adjacent infected cells an example of failure to propagate while three is not. However, it is tempting to think that establishing a latent infection which can be complemented later by different strains might contribute to the comparative ease with which influenza A can jump species barriers.

the later experiments using the california/09 and new caledonia/99 strains suggest that the effect is not an artifact of using lab strains, though it remains to be seen what unpassaged natural isolates would look like.
the image shown in figure 5 tries to show that productive and non-productive infections are clearly identifiable by eye, despite the seemingly arbitrary 2 cells vs. 3 cells cut-off.
it will be interesting to see the effect of this on mixing between different strains.

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Phenomena is a gathering of spirited science writers who take delight in the new, the strange, the beautiful and awe-inspiring details of our world. Phenomena is hosted by National Geographic magazine, which invites you to join the conversation. Follow on Twitter at @natgeoscience.

Ed Yong is an award-winning British science writer. Not Exactly Rocket Science is his hub for talking about the awe-inspiring, beautiful and quirky world of science to as many people as possible.
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